# Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $43,374

## Abstract

Project Summary
Chromatin-modifying enzymes that are associated with enhancer function are frequently mutated in human
craniofacial disorders. Kabuki syndrome (KS) is a craniofacial development disorder characterized by
mutations in KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase. Neural crest cells (NCCs) are the stem
cells from which anterior facial bone and cartilage originate. Our preliminary studies show that mouse NCC
deletion of KMT2D results in a lack of cranial base chondrocyte hypertrophic differentiation. As KS patients
present with skeletal defects that may result from abnormal chondrocyte differentiation, understanding the
mechanism of KMT2D function in this differentiation process is crucial to a better understanding of both
craniofacial and skeletal development disorders. This proposal will assess KMT2D’s molecular mechanism in
Aim 1 by interrogation of KMT2C/D-deficient NCCs in culture for changes in KMT2D genome binding,
chromatin accessibility, differential gene expression, and localization of histone-methylation at enhancer
regions utilizing genomic methodologies during chondrocyte differentiation. As previous publications have
indicated methylase-independent roles for KMT2D, this proposal will utilize KMT2D rescue constructs to
identify critical domains and non-enzymatic roles of KMT2D in cranial chondrocyte differentiation using
genomics and genetic approaches. Aim 2 will explore the cellular mechanism of chondrocyte-specific loss of
KMT2C/D on cranial base formation using histology, immunofluorescence, and other imaging approaches.
Long bone growth plates will also be examined in chondrocyte-specific KMT2D mutant mice for morphological
and molecular changes of chondrogenic differentiation markers to assay broader KMT2D-dependent
chondrocyte mechanisms. Collectively, this proposal will ascertain the novel functional roles that KMT2C and
KMT2D play in regulating chondrocyte differentiation and the results of this study will implicate epigenetic
modifiers in the progression and therapeutics of skeletal disease.

## Key facts

- **NIH application ID:** 10998935
- **Project number:** 1F31DE033916-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gabrielle Alair Quickstad
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,374
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998935

## Citation

> US National Institutes of Health, RePORTER application 10998935, Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification (1F31DE033916-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10998935. Licensed CC0.

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